The single was released in North America as the third single from "So" in the U.S., the song achieved strong radio airplay and a constant MTV rotation. It reached #1 on the BillboardMainstream Rock Tracks on September, 13 of the same year,[2] it also peaked #26 on the Billboard Hot 100 in November 1986.[3] It was not released as a single in the UK. However, Gabriel did release two extended versions of the song as a 12" vinyl single in the US. The first (the Single Mix) ran 6:15. The second (the Special Mix) ran 7:14.

The song was the finale of the Secret World Tour and is the final track on the 1994 Secret World Live album, where it is over 11 minutes long and includes the extra lyrics from the Special Mix, in addition to solos by the other singers and players. It was included on the U.S. version of his 2003 compilation Hit, but not on the European or Japanese versions.

In 2005, the song brought Gabriel his first Gold single, certified in the U.S. by the RIAA.[4]

The song was used twice in the 1989 US Cameron Crowe film, Say Anything..., as well as in its trailer. An iconic scene from the film occurs when broken-hearted Lloyd Dobler serenades his ex-girlfriend, Diane Court, outside her bedroom window by holding a boombox up above his head and playing the song for her. Repopularized by its usage in the film, the song reentered the US charts but narrowly failed to crack the top 40 in its second run, reaching as high as #41.[3] Peter Gabriel asked to see Crowe's film and Crowe asked the production company to send Gabriel a rough cut. Gabriel approved the use of his song, but told Crowe that he was uneasy about the overdose of the main character at the end; the studio had erroneously sent Gabriel the film Wired instead.[6]

The song's use in that iconic scene has been parodied in popular satirical shows. In the American Dad episode "It's Good to Be Queen", Stan Smith, in an attempt to get Francine to forgive him, forces Gabriel Byrne—whom he mistakenly believes to be Peter Gabriel—to sing "In Your Eyes" while holding the actor above his head. In the South Park episode "Raisins", when Wendy breaks up with Stan, Bebe tells him to hold up a boombox playing Peter Gabriel outside Wendy's window, to try to win her back. Instead of playing "In Your Eyes," he plays Gabriel's decidedly unromantic "Shock the Monkey".

In a September 2012 interview with Rolling Stone, discussing the 25th anniversary of So, Gabriel commented on the cultural impact of the scene, "It definitely gave [the song] a second life, because now it's so often parodied in comedy shows and it is one of the modern day Romeo and Juliet balcony clichés. I've talked to John Cusack about that. We're sort of trapped together in a minuscule moment of contemporary culture."[8] In October 2012, as Gabriel played the first few bars of the song during a performance at the Hollywood Bowl, Cusack walked onto the stage, handed him a boombox and took a bow, before quickly walking off again. Cameron Crowe was also present at the concert and later tweeted "Peter Gabriel and John Cusack on stage together at the Hollywood Bowl tonight. Won't forget that... ever."[9]

On April 10, 2014, Gabriel performed the song with an extended vocal duet with N'Dour as Gabriel was being inducted into the Rock and Roll Hall of Fame. The event, which took place at the Barclays Center in Brooklyn, NY, was filmed and was later televised in late May 2014 on the HBO cable channel.